Non-hormonal contraceptive method that is potent, safe, cost-effective, coitally-dissociated yet on-demand and can be self-administered remains lacking and sorely needed. We believe we can develop such contraception by drawing inspiration from mechanisms of immune-infertility, whereby sperm-binding antibodies (Ab) agglutinate and/or trap sperm in mucus and prevent spermatozoa from swimming through mucus and reaching the egg. Indeed, topical delivery of human contraceptive antibodies (HCA) can facilitate on-demand and instant contraception, and utilizes a mechanism that is not only naturally occurring in millions of women but also likely to be exceptionally safe. Although mucosal immune infertility was discovered in the 1970s, and demonstrated in animal models in the 1980s and 1990s, the concept of using Ab as a contraceptive and a microbicide was simply too far ahead of its time, due to the considerable real and perceived costs at that time that continue to this day. Given the remarkable advances in not only bioprocessing but also biotechnology over the past 2 decades, we believe the time is now ripe to develop different HCA constructs that possess superior agglutination potency compared to native IgG and costeffective to produce. In Aim 1, we will engineer two novel multimeric HCA constructs comprised of four intact Fab domains against male reproductive tract restricted antigen linked to a parent human IgG molecule. By incorporating multiple Fab domains while maintaining the Fc N-glycosylation profile, we believe we can engineer HCA with greater agglutination potency while retaining the ease of commercial manufacturing and purification of parent IgG1. We will also integrate our current work on harnessing IgG-mucin interactions to engineer HCA with Fc-N-glycan variants that facilitate effective trapping of individual sperm in mucus. In Aim 2, we will measure the muco-trapping potency of the HCA constructs in fresh human genital secretions. Successful completion of these studies will likely advance a novel HCA candidate with substantially greater contraceptive potency than the current lead HCA candidate based on human IgG1.